Copper-Catalyzed C-C Cross-Couplings of Tertiary Alkyl Halides with Anilines Enabled by Cyclopropenimine-Based Ligands

Catalytic cross-couplings of tertiary alkyl electrophiles with carbon nucleophiles offer a powerful platform for constructing quaternary carbon centers, which are prevalent in bioactive molecules. However, these reactions remain underdeveloped primarily because of steric challenges that impede efficient bond formation. Herein, we describe the copper-catalyzed synthesis of such centers through the C(sp(3))-C(sp(2)) bond-forming reaction between tertiary alkyl halides and arene rings of aniline derivatives, enabled by the strategic implementation of bidentate bis(cyclopropenimine) ligands. The copper catalyst bound by two imino-nitrogen atoms of these ligands, which have never been employed in metal catalysis previously, is highly effective in rapidly activating tertiary halides to generate alkyl radicals, allowing them to react with aryl nucleophiles under mild conditions with remarkably short reaction times (1-2 h). Various tertiary halides bearing carbonyl functional groups can be coupled with secondary or primary anilines, furnishing a range of quaternary carbon centers in good yields. Several mechanistic observations support the generation of copper(II) species and alkyl radicals which as a result elucidate the steps in the proposed catalytic cycle.

Automated summary

Copper-catalyzed synthesis of quaternary carbon centers through C(sp(3))-C(sp(2)) bond-forming reaction between tertiary alkyl halides and arene rings of aniline derivatives is enabled by the use of bidentate bis(cyclopropenimine) ligands. The copper catalyst, bound by imino-nitrogen atoms of these ligands, effectively activates tertiary halides to generate alkyl radicals and allows them to react with aryl nucleophiles under mild conditions with short reaction times. Various tertiary halides bearing carbonyl functional groups can be coupled with secondary or primary anilines to furnish quaternary carbon centers in good yields. Several mechanistic observations support the proposed catalytic cycle.